Prostate cancer is the most common malignancy and the second leading cause of cancer-related death in American men. Prostate cancer is a biologically and clinically heterogeneous disease. A majority of men with this malignancy harbor slow-growing tumors that may not impact an individual's natural lifespan, while others are struck by rapidly progressive, metastatic tumors. PSA screening is limited by a lack of specificity and an inability to predict which patients are at risk to develop hormone refractory metastatic disease. Recent studies advocating a lower PSA threshold for diagnosis may increase the number of prostate cancer diagnoses and further complicate the identification of patients with indolent vs. aggressive cancers (Punglia et al., N Engl J Med, 349: 335-342 (2003)). New serum and tissue markers that correlate with clinical outcome or identify patients with potentially aggressive disease are urgently needed (Welsh et al., Proc Natl Acad Sci USA, 100: 3410-3415 (2003)).
Recent expression profiling studies suggest that expression signatures for metastatic vs. non-metastatic tumors may reside in the primary tumor (Ramaswamy et al., Nat Genet, 33: 49-54 (2003); Sotiriou et al., Proc Natl Acad Sci USA, 100: 10393-10398 (2003)). Additional features that predispose tumors to metastasize to specific organs may also be present at some frequency in the primary tumor (Kang et al., Cancer Cell, 3: 537-549 (2003)). These recent observations suggest that novel markers of pre-metastatic or pre-hormone refractory prostate cancer may be identified in early stage disease. These markers may also play a role in the biology of metastatic or hormone refractory prostate cancer progression. Recent examples of genes present in primary tumors that correlate with outcome and play a role in the biology of prostate cancer progression include EZH2 and LIM kinase (Varambally et al., Nature, 419: 624-629 (2002); Yoshioka et al., Proc Natl Acad Sci USA, 100: 7247-7252 (2003)). However, neither of these two genes is secreted.
In order to identify new candidate serum or tissue markers of hormone refractory prostate cancer, we have previously compared gene expression profiles of paired hormone dependent and hormone refractory prostate cancer xenografts. The LAPC-9 xenograft was established from an osteoblastic bone metastasis and progresses from androgen dependence to independence following castration in immune deficient mice (Craft et al., Cancer Research, In Press (1999)). It has been used previously to identify candidate therapeutic targets in prostate cancer. Differentially expressed genes were validated and then examined for sequence homology to secreted or cell surface proteins. N-Cadherin has been identified as a marker of cancer. The identification, characterization and initial validation of N-Cadherin, which is expressed in both hormone refractory prostate cancer and bladder cancer, has been previously reported (WO/2007/109347).
One type of cell movement than can be observed in embryogenesis requires the loss of cell-cell contacts for the migration of individual cells or small group of cells through the extracellular matix. This process is called epithelial to mesenchymal transition (EMT). EMT also occurs in pathological situations, such as the acquisition of a motile and invasive phenotype of tumor cells of epithelial origin. A hallmark of EMT, is the loss of E-cadherin and the de novo expression of N-cadherin adhesion molecules. N-cadherin promotes tumor cell survival, migration and invasion, and high levels of N-cadherin expression is often associated with poor prognosis. N-cadherin is also expressed in endothelial cells and plays an essential role in the maturation and stabilization of normal vessels and tumor-associated angiogenic vessels. Increasing experimental evidence suggests that N-cadherin is a potential therapeutic target in cancer.
The function of N-cadherin has been studied at the molecular level. N-cadherin N-terminal extracellular region (160 to 724 a.a) consists of 5 domains (ECD1-ECD5). ECD1 and ECD2 are the minimal domains required for intracellular adhesion but if all extracellular domains are involved, the level of adhesion is strengthened. In addition a study has shown that a 69 amino acid portion of ECD4 was found to be essential in migration and mobility but not in cellular adhesion (Kimet al. J Cell Biol 2000).
Accordingly, the invention provides compositions and methods which target N-Cadherin in the diagnosis, prognosis, and treatment of cancers expressing N-Cadherin including, but not limited to, prostate cancer and bladder cancer. Antibodies, and fragments thereof, which are specific to the extracellular domains of N-cadherin, are also reported herein.